1h23

STRUCTURE OF ACETYLCHOLINESTERASE (E.C. 3.1.1.7) COMPLEXED WITH (S,S)-(-)-BIS(12)-HUPYRIDONE AT 2.15A RESOLUTION
(see also AChE bivalent inhibitors, 1h22, 1zgb, and 1zgc)



Superposition of the complexes of (R)-tacrine-(10)-hupyridone ((R)-3, cyan, PDB entry 1zgb) and (S,S)-(-)-Bis(12)-hupyridone ((S,S)-(-)-4b, orange, i.e. 12-carbon-tether-linked hupyridone dimer, 1h23) and (S,S)-(-)-Bis(10)-hupyridone ((S,S)-(-)-4a, plum, 1h22) with TcAChE demonstrates the binding mode of the hupyridone moiety. The TcAChE residues of symmetry-related molecule are shown in magenta. X-ray structures of TcAChE complexed with these 10- and 12-carbon-tether-linked bifunctional inhibitors (S,S)-(-)-4a and (S,S)-(-)-4b show one moiety bound at the CAS, the linker spanning the gorge, and the other moiety bound at the PAS. There are two hydrogen bonds connecting the hupyridone O to Lys11 Nζ and <font color='cyan'>hupyridone <font color='blue'>N to <font color='magenta'>Gln185 <font color='red'>Oε1 of a <font color='magenta'>symmetry-related molecule of the <font color='cyan'>(R)-3 /TcAChE complex. <font color='red'>Water molecules are shown as red spheres. Another hydrogen bond connects the <font color='cyan'>hupyridone <font color='red'>O to a water molecule, which is bound to Ser286 N. Similarly, the hupyridone at the PAS site of both <font color='plum'>(-)-4a and <font color='orange'>(-)-4b forms direct and water-mediated hydrogen bonds with the protein backbone.

About this Structure
1H23 is a Single protein structure of sequence from Torpedo californica. Full crystallographic information is available from OCA.

Additional Resources
For additional information, see: Alzheimer's Disease

Reference
Acetylcholinesterase complexed with bivalent ligands related to huperzine a: experimental evidence for species-dependent protein-ligand complementarity., Wong DM, Greenblatt HM, Dvir H, Carlier PR, Han YF, Pang YP, Silman I, Sussman JL, J Am Chem Soc. 2003 Jan 15;125(2):363-73. PMID:12517147

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